R. SchulzG. Heusch

Balance and imbalanceof regional myocardial contractile functionand blood flow

Z Kardiol 90:964–969 (2001)© Steinkopff Verlag 2001

ZFK

754

Eingegangen: 24. Oktober 2000Akzeptiert: 22. März 2001

Hauptvortrag,gehalten auf der 66. Jahrestagungder Deutschen Gesellschaftfür Kardiologie –Herz- und Kreislaufforschung27. bis 29. April 2000 in Mannheim

Prof. Dr. Rainer Schulz ())Prof. Dr. Dr. h.c. Gerd HeuschAbteilung für PathophysiologieZentrum für Innere MedizinUniversitätsklinikum EssenHufelandstraße 5545122 Essen, Germany

Gleichgewicht und Ungleichgewichtzwischen regionaler myokardialerFunktion und Durchblutung

n Zusammenfassung WährendNormoperfusion sind kontraktileFunktion und regionale myokar-diale Durchblutung über den lin-ken Ventrikel heterogen verteilt.Die mittmyokardiale Segmentlän-genverkürzung ist an der Herzba-sis größer als an der Herzspitzeund in der Vorderwand größerals in der Hinterwand des linkenVentrikels. Auch transmural istdie myokardiale Deformation he-terogen ausgeprägt, mit einerstärkeren Segmentlängenverkür-

zung oder Wandverdickung inden Innenschichten als in denAußenschichten des Myokards.Die regionale myokardiale Durch-blutung ist ebenfalls in den In-nenschichten höher als in denAußenschichten. Neben der trans-muralen Heterogenität bestehenauch Unterschiede in der regiona-len Durchblutung in Ruhe zwi-schen benachbarten Myokard-arealen. Während eine Zunahmeder myokardialen kontraktilenFunktion von einem metabolischvermittelten Anstieg der regiona-len myokardialen Durchblutunggefolgt ist, ist eine Steigerung derregionalen Durchblutung inner-halb des autoregulatorischen Be-reichs nicht von einer Zunahmeder systolischen Wandexkursionbegleitet.

Während Hypoperfusion, indu-ziert durch eine proximale Koro-narstenose, ist die Reduktion dersubendokardialen Durchblutungstärker ausgeprägt als die dersubepikardialen Durchblutung,und die kontraktile Funktion derInnenschichten kommt rascher alsdie der Außenschichten der Myo-kards zum Erliegen. Die reduziertemyokardiale kontraktile Funktionist eng an die reduzierte myokar-diale Durchblutung gekoppelt(„perfusion-contraction match-ing“); diese Kopplung zwischender reduzierten Durchblutung undFunktion geht aber mit einer Ver-

längerung der Ischämie auf meh-rere Stunden verloren, d.h. dieFunktion für eine gegebeneDurchblutung nimmt weiter ab.Ein akuter embolischer Verschlußder koronaren Mikrostrombahninduziert einen fortschreitendenVerlust der regionalen myokardia-len Funktion bei unveränderterregionaler myokardialer Durch-blutung, d.h. ein „perfusion-con-traction mismatch“. An der fort-schreitenden Reduktion der Wan-dexkursion ist eine inflammatori-sche Reaktion beteiligt.

Während Reperfusion bleibt dieregionale myokardiale kontraktileFunktion über einen langen Zeit-raum in Abhängigkeit von Schwe-regrad, Dauer und Lokalisationder vorangegangenen Ischämieeingeschränkt, während die regio-nale myokardiale Durchblutungvollständig oder nahezu vollstän-dig wiederhergestellt ist.

n SchlüsselwörterDurchblutung –kontraktile Funktion –Hibernation – Stunning –Mikroembolisation

n Summary During normoperfu-sion, both contractile functionand myocardial blood flow areheterogeneously distributedthroughout the left ventricle.Midwall segment shortening isgreater at the apex than at the

MYOCARD

965R. Schulz and G. HeuschBalance and imbalance of regional myocardial contractile function and blood flow

base of the left ventricle, and it isgreater in the anterior than in theposterior wall. Also, transmuralheterogeneity of myocardial de-formation exists, with greater seg-ment shortening and wall thick-ening in inner than in outer myo-cardial layers. Myocardial bloodflow is greater in inner than inouter myocardial layers. Apartfrom transmural heterogeneities,there are adjacent regions withlargely different resting flow inthe same heart. While an increasein myocardial contractile functionwill lead to a metabolicallymediated increase in myocardialblood flow, an increase in regionalcoronary perfusion within or

above the autoregulatory rangedoes not, in turn, increase regionalmyocardial contractile function.During hypoperfusion induced by aproximal coronary stenosis, thereduction in subendocardial bloodflow is more pronounced than thatin subepicardial blood flow, andcontractile function in the innermyocardial layers ceases morerapidly than that in outer myo-cardial layers. The reduced re-gional myocardial contractilefunction is closely matched to thereduced regional myocardial bloodflow; however, such coupling be-tween reduced flow and function islost when ischemia is prolongedfor several hours, i.e., function for

a given flow is further reduced.Acute embolization of the coronarymicrocirculation induces a pro-gressive loss of regional myocar-dial function at unchanged re-gional myocardial blood flow, i.e.,perfusion-contraction mismatch.During reperfusion, regional myo-cardial contractile function re-mains depressed for a prolongedperiod of time, depending on theseverity, duration and location ofthe preceding ischemic epsiode,while regional myocardial bloodflow is restored.

n Key words Blood flow –contractile function–hibernation–stunning – microembolization

Regional myocardial perfusionand contractile functionunder physiological conditions

There is a remarkable spatial heterogeneity of bothmyocardial deformation and perfusion. Segmentshortening is higher at the apex than at the base(29), and it is higher in the anterior than in the pos-terior left ventricular wall (28). In addition to thelateral dispersion of myocardial deformation, thereis transmural nonuniformity of myocardial deforma-tion, with greater segment shortening (16) and wallthickening in inner than in outer myocardial layers(17). Similarly, both circumferential and longitudinalfiber strains increase from the subepicardium tosubendocardium (44). Thus, it appears that a hetero-geneity in transmural deformation is present duringnormoperfusion; whether or not the transmural dis-tribution of local wall stress is similar remains un-known at present.

A spatial heterogeneity of myocardial blood flowexists (3), which is not simply related to temporal fluc-tuations since the heterogeneous flow pattern is stableover at least a few minutes (3, 39). The spatial hetero-geneity of resting myocardial blood flow is not corre-lated to the heterogeneity of maximal myocardialblood flow during pharmacological recruitment ofcoronary reserve. A study directly comparing the spa-tial distribution of regional myocardial contractilefunction and perfusion is not available, since thereis currently no method to measure contractile func-tion at a similar spatial resolution (about 100 mg).However, the spatial heterogeneity of blood flow cor-relates to that of oxidative metabolism (38).

While an increase in myocardial contractile func-tion (energy demand) will lead to a metabolicallymediated increase in myocardial blood flow (energysupply) to keep energy demand and supply in bal-ance, several studies suggested that increases in cor-onary perfusion per se (Gregg phenomenon (18))within or above the coronary autoregulatory rangealso increase myocardial contractile function. The“gardenhose” hypothesis states that increasing intra-vascular pressure distends the myocardial vesselswhich, in turn, stretch adjacent myocardial fibers(2), thus, implying a local Frank-Starling mecha-nism. While on a global ventricular level, the exis-tence of a Gregg or gardenhose phenomenon re-mains controversial, there is no evidence for the ex-istence of a Gregg or gardenhose phenomenon on aregional myocardial level as long as autoregulation isoperative (36).

Regional myocardial perfusionand contractile functionduring acute coronary inflow reduction

Upon acute coronary artery occlusion, contractilefunction in the ischemic region rapidly ceases. With-in a few cardiac cycles, systolic segment shorteningand systolic wall thickening are reduced (hypokin-esis), later abolished (akinesis) and within 30 s to2 min replaced by paradoxic systolic segment length-ening and systolic wall thinning (dyskinesis, bul-ging) (42). Similarly, circumferential and longitudi-nal fiber strains decrease within 10 min of coronary

artery occlusion, and a transmural gradient of fiberstrain is no longer present (44). The underlyingmechanisms for the rapid loss of contractile func-tion in ischemic myocardium remain unclear (for re-view see (20)). Two to three minutes after the onsetof ischemia, there is a consistent relationship be-tween the reduced regional myocardial blood flowand reduced contractile function, as assessed by sys-tolic wall thickening or segment shortening (14, 15,43) (Fig. 1). Thus, any reduction in regional myocar-dial blood flow, i.e., the major determinant of energysupply, is associated with an appropriate reductionin regional myocardial function, i.e., the major de-terminant of energy demand. Therefore, a transientstate of imbalance between supply and demand mayexist, but only during the first few minutes of devel-oping ischemia after coronary occlusion. A similartransient state of supply-demand imbalance may alsoexist during the onset of exercise-induced ischemiawhen regional myocardial contractile function anddemand are transiently increased but coronary in-flow and thus supply is limited by a critical coronarystenosis. However, during steady-state (2–3 min afteronset) exercise-induced myocardial ischemia, region-al blood flow and contractile function are also re-duced in parallel, i.e., they display a proportionaterelationship, indicating appropriate matching offunction to flow (15). The relationship between isch-emic regional myocardial blood flow and functionvaries with the hemodynamic situation. During exer-cise in conscious dogs with different degrees of cor-onary stenosis, the relationship between systolic wallthickening and subendocardial or transmural myo-cardial blood flow is shifted. There is a higher bloodflow for a given level of function during exercise ascompared to resting conditions (15). When myocar-dial blood flow is normalized for heart rate, i.e., ex-

pressed as blood flow per beat rather than bloodflow per minute, the relationships at rest and duringexercise are superimposable. Similarly, in an an-esthetized swine model with constant-flow coronaryhypoperfusion, the relationship between systolic wallthickening and subendocardial blood flow per min-ute is shifted to lower function values at increasedheart rate; however, the relationships of systolic wallthickening and subendocardial blood flow per beatare superimposable and independent of heart rate(26).

Prolonged regional ischemia

With severe myocardial ischemia resulting fromcomplete coronary occlusion, irreversible damagestarts to develop after 20–40 min; the infarct devel-ops as a transmural wavefront from the most isch-emic subendocardial to the less ischemic subepicar-dial layers (32, 33). However, with more moderatenon-transmural ischemia, both regional myocardialblood flow and systolic wall thickening may be re-duced by about 50% for 5 hours without evidence ofirreversible damage and gradual, but complete recov-ery of function over 1 week after reperfusion (31).Thus, a balance between supply and demand maynot only exist during early steady-state ischemia (seeabove) but also during hours of ischemia. A bal-anced reduction of regional blood flow and contrac-tile function over a prolonged period of time in vi-able myocardium is one essential feature of short-term hibernation (21, 34).

966 Zeitschrift für Kardiologie, Band 90, Heft 12 (2001)© Steinkopff Verlag 2001

Fig. 1 Close relation between regional myocardial blood flow and function.From (14) by permission of the American Physiological Society

Fig. 2 Endogenous nitric oxide (NO) improves contractile function for anygiven blood flow. The relationship between contractile function (externalwork index) and transmural blood flow is shifted to the right followingblockade of NO synthase with L-NA. Matching the increase in blood pressure,as seen following L-NA, by aortic constriction (AO) does not influence theregional blood flow-contractile function relationship. P-value indicates signifi-cant difference of relationship with L-NA from both placebo and AO. Symbolsrepresent mean values (±SEM) before and at 10 min and 85 min ischemia(from (23))

Endogenous nitric oxide affects the regionalblood flow-function relationship, in that it acts topreserve calcium sensitivity during ongoing ischemiaand thereby improves contractile function for anygiven blood flow (Fig. 2). This increase in contractilefunction is without any additional impact on myo-cardial energetic state (23).

When ischemia is prolonged for 24 hours in theanesthetized swine, regional myocardial contractilefunction is progressively further reduced at constantflow, with apparent loss of perfusion-contractionmatching, suggesting that additional factors – in-itiated during ongoing ischemia – act to reduce re-gional contractile function. In contrast, the matchingbetween regional myocardial contractile functionand regional myocardial oxygen consumption is stillmaintained even after 24 hours of ischemia, support-ing the concept of metabolic adaptation to prolongedhypoperfusion (37).

Coronary microembolization

Coronary microembolization secondary to sponta-neous (4, 11, 12) or therapeutic (9, 35) plaque rup-ture occurs clinically and is of pathophysiologicalsignificance in acute coronary syndromes (11, 13,30). In anesthetized dogs, intracoronary microembo-lization induces a progressive reduction in regionalfunction without a decrease in regional blood flow(spatial resolution of 300 mg), i.e., there is perfu-sion-contraction mismatch (Fig. 3). The total area ofnecrosis resulting from such microembolization isprobably too small to account for this progressive

dysfunction (10). Coronary microembolization re-sults in leukocyte infiltration, and inflammatorymediators may be responsible for the observed dys-function.

Regional myocardial perfusionand function during reperfusion

Brief periods of myocardial ischemia not causing irre-versible damage may nevertheless result in a pro-longed impairment of contractile function upon, i.e.,“stunning” (25). Almost by definition, the close rela-tionship of reduced myocardial blood flow and con-tractile function observed during ischemia is alteredduring reperfusion, as blood flow is restored and con-tractile function remains depressed. Although suben-docardial blood flow in stunned myocardium may be– after a period of reactive hyperemia – somewhat re-duced (7, 19, 24), this finding is not consistent (27,40). A causal involvement of a persistent subendocar-dial blood flow reduction in the prolonged impair-ment of regional contractile function appears unlikely(5). Also, refuting the causal involvement of a reduc-tion in blood flow for myocardial stunning, there isno consistent relationship between regional myocar-dial blood flow and function in stunned myocardiumduring reperfusion (1, 7, 31, 41) (Fig. 4).

Whereas there is no apparent relationship of re-gional myocardial blood flow and contractile func-tion in stunned myocardium during reperfusion,there is a relationship between regional myocardialcontractile function during reperfusion and the se-verity of regional myocardial blood flow reductionduring the preceding ischemia. The rate of recoveryof function in stunned myocardium during 24 hours

967R. Schulz and G. HeuschBalance and imbalance of regional myocardial contractile function and blood flow

Fig. 3 Relationships between normalized posterior transmural blood flow(PTBF) and normalized posterior systolic wall thickening (PWT) during pro-gressive coronary stenosis (�) and following microembolization (�) at con-trol, 1, 4, and 8 hours (h) of ischemia. Values are mean ±SD. In the coro-nary stenosis group but not in the microembolization group, there was agood linear relationship between PWT and and PTBF (y=0.90 · x–0.07,r=0.82, solid line). Values are mean ± SD (from (10))

Fig. 4 Relationship of subendocardial blood flow and systolic wall thicken-ing at rest (A), during exercise-induced ischemia (B), and at 5 (C), 10 (D)and 30 min (E) after the end of exercise. During recovery from exercise-in-duced ischemia, regional myocardial blood flow and function are largely un-coupled. From (41) by permission of the American Physiological Society

of reperfusion depends on the severity of blood flowreduction during the 15 minutes of the precedingischemia (8). Function in the inner myocardial layerswhere ischemia is more severe recovers more slowlythan that of outer, less ischemic myocardial layers(6). Dependence of postischemic dysfunction on the

severity of the preceding reduction in blood flowper beat was also demonstrated during recoveryfrom a bout of exercise-induced ischemia (22).Whether or not heterogeneity of contractile functionexists in reperfused “stunned” myocardium, remainsunclear at present.

968 Zeitschrift für Kardiologie, Band 90, Heft 12 (2001)© Steinkopff Verlag 2001

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